tbuckley/cabot-search huggingface dataset:
COVID-19 and Kidney Disease
Authors: Maureen Brogan, Michael J. Ross
Journal: Annual Review of Medicine (2022)

COVID-19 can cause acute kidney injury and may cause or exacerbate chronic kidney diseases, including glomerular diseases. SARS-CoV-2 infection of kidney cells has been reported, but it remains unclear if viral infection of kidney cells causes disease. The most important causes of kidney injury in patients with COVID-19 include impaired renal perfusion and immune dysregulation. Chronic kidney disease, especially kidney failure with kidney replacement therapy and kidney transplant, is associated with markedly increased COVID-19 mortality. Persons with severe kidney disease have been excluded from most clinical trials of COVID-19 therapies, so therapeutic approaches must be extrapolated from studies of patients without kidney disease. Some medications used to treat COVID-19 should be avoided or used at reduced dosages in patients with severe kidney disease and in kidney transplant recipients. Additional research is needed to determine the optimal strategies to prevent and treat COVID-19 in patients with kidney disease.
Mitochondrial Genomes in<i>Perkinsus</i>Decode Conserved Frameshifts in All Genes
Authors: Sebastian G Gornik, Victor Flores, Franziska Reinhardt, Lieselotte Erber, Dayana E Salas-Leiva, Olga Douvropoulou, Imen Lassadi, Elin Einarsson, Mario Mörl, Anna Git, Peter F Stadler, Arnab Pain, Ross F Waller
Journal: Molecular Biology and Evolution (2022)

Abstract Mitochondrial genomes of apicomplexans, dinoflagellates, and chrompodellids that collectively make up the Myzozoa, encode only three proteins (Cytochrome b [COB], Cytochrome c oxidase subunit 1 [COX1], Cytochrome c oxidase subunit 3 [COX3]), contain fragmented ribosomal RNAs, and display extensive recombination, RNA trans-splicing, and RNA-editing. The early-diverging Perkinsozoa is the final major myzozoan lineage whose mitochondrial genomes remained poorly characterized. Previous reports of Perkinsus genes indicated independent acquisition of non-canonical features, namely the occurrence of multiple frameshifts. To determine both ancestral myzozoan and novel perkinsozoan mitochondrial genome features, we sequenced and assembled mitochondrial genomes of four Perkinsus species. These data show a simple ancestral genome with the common reduced coding capacity but disposition for rearrangement. We identified 75 frameshifts across the four species that occur as distinct types and that are highly conserved in gene location. A decoding mechanism apparently employs unused codons at the frameshift sites that advance translation either +1 or +2 frames to the next used codon. The locations of frameshifts are seemingly positioned to regulate protein folding of the nascent protein as it emerges from the ribosome. The cox3 gene is distinct in containing only one frameshift and showing strong selection against residues that are otherwise frequently encoded at the frameshift positions in cox1 and cob. All genes lack cysteine codons implying a reduction to 19 amino acids in these genomes. Furthermore, mitochondrion-encoded rRNA fragment complements are incomplete in Perkinsus spp. but some are found in the nuclear DNA suggesting import into the organelle. Perkinsus demonstrates further remarkable trajectories of organelle genome evolution including pervasive integration of frameshift translation into genome expression.
Steatosis, HBV‐related HCC, cirrhosis, and HBsAg seroclearance: A systematic review and meta‐analysis
Authors: Xianhua Mao, Ka Shing Cheung, Chengzhi Peng, Lung‐Yi Mak, Ho Ming Cheng, James Fung, Noam Peleg, Howard H.‐W. Leung, Rajneesh Kumar, Jeong‐Hoon Lee, Amir Shlomai, Man‐Fung Yuen, Wai‐Kay Seto
Journal: Hepatology (2022)

Background and Aims: NAFLD and chronic hepatitis B (CHB) infection are common etiologies of HCC. The impact of hepatic steatosis on HCC in CHB, as well as its relationship with the development of cirrhosis, fibrosis, and HBsAg seroclearance, remains controversial. Approach and Results: Data from observational studies were collected through PubMed, EMBASE, and the Cochrane Library from inception to February 1, 2022. Outcomes of interest included the association of hepatic steatosis with HCC, cirrhosis, advanced fibrosis, and HBsAg seroclearance, expressed in terms of pooled ORs. Additional subgroup and sensitivity analyses were performed to validate the robustness of findings. A total of 34 studies with 68,268 patients with CHB were included. Hepatic steatosis was associated with higher odds of HCC (OR, 1.59; 95% CI, 1.12–2.26; I 2 = 72.5%), with the association remaining consistent in Asia (OR, 1.56; 95% CI, 1.08–2.25), studies with a median follow‐up duration of ≥5 years (OR, 2.82; 95% CI, 1.57–5.08), exclusion of alcohol use (OR, 1.71; 95% CI, 1.01–2.91), and biopsy‐proven steatosis (OR, 2.86; 95% CI, 1.61–5.06), although no significant association was noted among nucleos(t)ide analogue–treated patients (OR, 1.05; 95% CI, 0.62–1.77). Steatosis was associated with the development of cirrhosis (OR, 1.52; 95% CI, 1.07–2.16; I 2 = 0%) and HBsAg seroclearance (OR, 2.22; 95% CI, 1.58–3.10; I 2 = 49.0%). Conclusions: Hepatic steatosis was associated with an increased risk of HCC and cirrhosis among patients with CHB but with a higher chance of achieving a functional cure, highlighting the importance of identifying concomitant steatosis in CHB.
Exposure Contrasts of Pregnant Women during the Household Air Pollution Intervention Network Randomized Controlled Trial
Authors: Michael Johnson, Ajay Pillarisetti, Ricardo Piedrahita, Kalpana Balakrishnan, Jennifer L. Peel, Kyle Steenland, Lindsay J. Underhill, Ghislaine Rosa, Miles A. Kirby, Anaité Díaz-Artiga, John McCracken, Maggie L. Clark, Lance Waller, Howard H. Chang, Jiantong Wang, Ephrem Dusabimana, Florien Ndagijimana, Sankar Sambandam, Krishnendu Mukhopadhyay, Katherine A. Kearns, Devan Campbell, Jacob Kremer, Joshua P. Rosenthal, William Checkley, Thomas Clasen, Luke Naeher
Journal: Environmental Health Perspectives (2022)

Background: Exposure to PM2.5 arising from solid fuel combustion is estimated to result in ∼2.3 million premature deaths and 91 million lost disability-adjusted life years annually. Interventions attempting to mitigate this burden have had limited success in reducing exposures to levels thought to provide substantive health benefits. Objectives: This paper reports exposure reductions achieved by a liquified petroleum gas (LPG) stove and fuel intervention for pregnant mothers in the Household Air Pollution Intervention Network (HAPIN) randomized controlled trial. Methods: The HAPIN trial included 3,195 households primarily using biomass for cooking in Guatemala, India, Peru, and Rwanda. Twenty-four-hour exposures to PM2.5, carbon monoxide (CO), and black carbon (BC) were measured for pregnant women once before randomization into control (n=1,605) and LPG (n=1,590) arms and twice thereafter (aligned with trimester). Changes in exposure were estimated by directly comparing exposures between intervention and control arms and by using linear mixed-effect models to estimate the impact of the intervention on exposure levels. Results: Median postrandomization exposures of particulate matter (PM) with aerodynamic diameter ≤2.5μm (PM2.5) in the intervention arm were lower by 66% at the first (71.5 vs. 24.1 μg/m3), and second follow-up visits (69.5 vs. 23.7 μg/m3) compared to controls. BC exposures were lower in the intervention arm by 72% (9.7 vs. 2.7 μg/m3) and 70% (9.6 vs. 2.8 μg/m3) at the first and second follow-up visits, respectively, and carbon monoxide exposure was 82% lower at both visits (1.1 vs. 0.2 ppm) in comparison with controls. Exposure reductions were consistent over time and were similar across research locations. Discussion: Postintervention PM2.5 exposures in the intervention arm were at the lower end of what has been reported for LPG and other clean fuel interventions, with 69% of PM2.5 samples falling below the World Health Organization Annual Interim Target 1 of 35 μg/m3. This study indicates that an LPG intervention can reduce PM2.5 exposures to levels at or below WHO targets. https://doi.org/10.1289/EHP10295
Identifying major impact factors affecting the continuance intention of mHealth: a systematic review and multi-subgroup meta-analysis
Authors: Tong Wang, Wei Wang, Jun Liang, Mingfu Nuo, Qinglian Wen, Wei Wei, Hongbin Han, Jianbo Lei
Journal: npj Digital Medicine (2022)

Abstract The mobile health (mHealth) industry is an enormous global market; however, the dropout or continuance of mHealth is a major challenge that is affecting its positive outcomes. To date, the results of studies on the impact factors have been inconsistent. Consequently, research on the pooled effects of impact factors on the continuance intention of mHealth is limited. Therefore, this study aims to systematically analyze quantitative studies on the continuance intention of mHealth and explore the pooled effect of each direct and indirect impact factor. Until October 2021, eight literature databases were searched. Fifty-eight peer-reviewed studies on the impact factors and effects on continuance intention of mHealth were included. Out of the 19 direct impact factors of continuance intention, 15 are significant, with attitude (β = 0.450; 95% CI: 0.135, 0.683), satisfaction (β = 0.406; 95% CI: 0.292, 0.509), health empowerment (β = 0.359; 95% CI: 0.204, 0.497), perceived usefulness (β = 0.343; 95% CI: 0.280, 0.403), and perceived quality of health life (β = 0.315, 95% CI: 0.211, 0.412) having the largest pooled effect coefficients on continuance intention. There is high heterogeneity between the studies; thus, we conducted a subgroup analysis to explore the moderating effect of different characteristics on the impact effects. The geographic region, user type, mHealth type, user age, and publication year significantly moderate influential relationships, such as trust and continuance intention. Thus, mHealth developers should develop personalized continuous use promotion strategies based on user characteristics.
CRISPR/dCas9-Dnmt3a-mediated targeted DNA methylation of APP rescues brain pathology in a mouse model of Alzheimer’s disease
Authors: Hanseul Park, Jaein Shin, Yunkyung Kim, Takashi Saito, Takaomi C. Saido, Jongpil Kim
Journal: Translational Neurodegeneration (2022)

Aberrant DNA methylation patterns have been observed in neurodegenerative diseases, including Alzheimer's disease (AD), and dynamic changes in DNA methylation are closely associated with the onset and progression of these diseases. Particularly, hypomethylation of the amyloid precursor protein gene (APP) has been reported in patients with AD.In this study, we used catalytically inactivated Cas9 (dCas9) fused with Dnmt3a for targeted DNA methylation of APP, and showed that the CRISPR/dCas9-Dnmt3a-mediated DNA methylation system could efficiently induce targeted DNA methylation of APP both in vivo and in vitro.We hypothesized that the targeted methylation of the APP promoter might rescue AD-related neuronal cell death by reducing APP mRNA expression. The cultured APP-KI mouse primary neurons exhibited an altered DNA-methylation pattern on the APP promoter after dCas9-Dnmt3a treatment. Likewise, the APP mRNA level was significantly reduced in the dCas9-Dnmt3a-treated wild-type and APP-KI mouse primary neurons. We also observed decreased amyloid-beta (Aβ) peptide level and Aβ42/40 ratio in the dCas9-Dnmt3a-treated APP-KI mouse neurons compared to the control APP-KI mouse neurons. In addition, neuronal cell death was significantly decreased in the dCas9-Dnmt3a-treated APP-KI mouse neurons. Furthermore, the in vivo methylation of APP in the brain via dCas9-Dnmt3a treatment altered Aβ plaques and attenuated cognitive and behavioral impairments in the APP-KI mouse model.These results suggest that the targeted methylation of APP via dCas9-Dnmt3a treatment can be a potential therapeutic strategy for AD.
Monocyte Recruitment for Vascular Tissue Regeneration
Authors: Bita Nasiri, Tai Yi, Yulun Wu, Randall J. Smith, Ashis Kumar Podder, Christopher K. Breuer, Stelios T. Andreadis
Journal: Advanced Healthcare Materials (2022)

Abstract A strategy to recruit monocytes (MCs) from blood to regenerate vascular tissue from unseeded (cell‐free) tissue engineered vascular grafts is presented. When immobilized on the surface of vascular grafts, the fusion protein, H2R5 can capture blood‐derived MC under static or flow conditions in a shear stress dependent manner. The bound MC turns into macrophages (M ϕ ) expressing both M1 and M2 phenotype specific genes. When H2R5 functionalized acellular‐tissue engineered vessels (A‐TEVs) are implanted into the mouse aorta, they remain patent and form a continuous endothelium expressing both endothelial cell (EC) and MC specific proteins. Underneath the EC layer, multiple cells layers are formed coexpressing both smooth muscle cell (SMC) and MC specific markers. Lineage tracing analysis using a novel CX3CR1‐confetti mouse model demonstrates that fluorescently labeled MC populates the graft lumen by two and four weeks postimplantation, providing direct evidence in support of MC/M ϕ recruitment to the graft lumen. Given their abundance in the blood, circulating MCs may be a great source of cells that contribute directly to the endothelialization and vascular wall formation of acellular vascular grafts under the right chemical and biomechanical cues.
Pilot Study of ONCOS-102 and Pembrolizumab: Remodeling of the Tumor Microenvironment and Clinical Outcomes in Anti–PD-1–Resistant Advanced Melanoma
Authors: Alexander N. Shoushtari, Anthony J. Olszanski, Marta Nyakas, Thomas J. Hornyak, Jedd D. Wolchok, Victor Levitsky, Lukasz Kuryk, Thomas B. Hansen, Magnus Jäderberg
Journal: Clinical Cancer Research (2022)

Intratumoral oncolytic virotherapy may overcome anti-PD(L)-1 resistance by triggering pro-inflammatory remodeling of the tumor microenvironment. This pilot study investigated ONCOS-102 (oncolytic adenovirus expressing GM-CSF) plus anti-programmed cell death protein 1 (PD)-1 therapy in anti-PD-1-resistant melanoma.Patients with advanced melanoma progressing after prior PD-1 blockade received intratumoral ONCOS-102 either as priming with 3 doses (3 × 1011 viral particles) during Week 1 [Part 1 (sequential treatment)] or as 4-dose priming and 8 booster doses every 3 weeks [Part 2 (combination treatment)]. From Week 3, all patients received pembrolizumab every 3 weeks (≤8 doses). The primary endpoint was safety. Objective response rate (ORR), progression-free survival, and immunologic activation in repeat biopsies were also investigated.In 21 patients (Part 1, n = 9; Part 2, n = 12) ONCOS-102 plus pembrolizumab was well tolerated: most adverse events (AE) were mild/moderate in severity. Pyrexia (43%), chills (43%), and nausea (28%) were the most common ONCOS-102-related AEs. There were no dose-limiting toxicities. ORR was 35% [response evaluation in solid tumors (RECIST) 1.1, irRECIST]. Reduction in size of ≥1 non-injected lesions observed in 53% patients indicated a systemic effect. In injected tumors, persistent immune-related gene expression and T-cell infiltration were associated with clinical benefit. Viral persistence and efficacy in injected and non-injected lesions without additional toxicity supported Part 2 dosing regimen in future studies.ONCOS-102 plus pembrolizumab was well tolerated and led to objective responses in patients with anti-PD-1-resistant advanced melanoma. ONCOS-102 promoted T-cell infiltration, particularly cytotoxic CD8+ T cells, which persisted at Week 9, driving clinical benefit. Further investigation of ONCOS-102 plus PD-1 blockade is warranted. See related commentary by Levi and Boland, p. 3.
Serial Profiling of Circulating Tumor DNA Identifies Dynamic Evolution of Clinically Actionable Genomic Alterations in High-Risk Neuroblastoma
Authors: Kristopher R. Bosse, Anna Maria Giudice, Maria V. Lane, Brendan McIntyre, Patrick M. Schürch, Guillem Pascual-Pasto, Samantha N. Buongervino, Sriyaa Suresh, Alana Fitzsimmons, Adam Hyman, Maria Gemino-Borromeo, Jennifer Saggio, Esther R. Berko, Alexander A. Daniels, Jennifer Stundon, Megan Friedrichsen, Xin Liu, Matthew L. Margolis, Marilyn M. Li, Marni Brisson Tierno, Geoffrey R. Oxnard, John M. Maris, Yael P. Mossé
Journal: Cancer Discovery (2022)

Neuroblastoma evolution, heterogeneity, and resistance remain inadequately defined, suggesting a role for circulating tumor DNA (ctDNA) sequencing. To define the utility of ctDNA profiling in neuroblastoma, 167 blood samples from 48 high-risk patients were evaluated for ctDNA using comprehensive genomic profiling. At least one pathogenic genomic alteration was identified in 56% of samples and 73% of evaluable patients, including clinically actionable ALK and RAS-MAPK pathway variants. Fifteen patients received ALK inhibition (ALKi), and ctDNA data revealed dynamic genomic evolution under ALKi therapeutic pressure. Serial ctDNA profiling detected disease evolution in 15 of 16 patients with a recurrently identified variant-in some cases confirming disease progression prior to standard surveillance methods. Finally, ctDNA-defined ERRFI1 loss-of-function variants were validated in neuroblastoma cellular models, with the mutant proteins exhibiting loss of wild-type ERRFI1's tumor-suppressive functions. Taken together, ctDNA is prevalent in children with high-risk neuroblastoma and should be followed throughout neuroblastoma treatment. ctDNA is prevalent in children with neuroblastoma. Serial ctDNA profiling in patients with neuroblastoma improves the detection of potentially clinically actionable and functionally relevant variants in cancer driver genes and delineates dynamic tumor evolution and disease progression beyond that of standard tumor sequencing and clinical surveillance practices. See related commentary by Deubzer et al., p. 2727. This article is highlighted in the In This Issue feature, p. 2711.
A review of brain imaging biomarker genomics in Alzheimer’s disease: implementation and perspectives
Authors: Lanlan Li, Xianfeng Yu, Can Sheng, Xueyan Jiang, Qi Zhang, Ying Han, Jiehui Jiang
Journal: Translational Neurodegeneration (2022)

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease with phenotypic changes closely associated with both genetic variants and imaging pathology. Brain imaging biomarker genomics has been developed in recent years to reveal potential AD pathological mechanisms and provide early diagnoses. This technique integrates multimodal imaging phenotypes with genetic data in a noninvasive and high-throughput manner. In this review, we summarize the basic analytical framework of brain imaging biomarker genomics and elucidate two main implementation scenarios of this technique in AD studies: (1) exploring novel biomarkers and seeking mutual interpretability and (2) providing a diagnosis and prognosis for AD with combined use of machine learning methods and brain imaging biomarker genomics. Importantly, we highlight the necessity of brain imaging biomarker genomics, discuss the strengths and limitations of current methods, and propose directions for development of this research field.
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Journal: JAMA Network Open (2022)

Eduardo R. Núñez, MD; Tanner J. Caverly, MD, MPH; Sanqian Zhang, PhD; Mark E. Glickman, PhD; Shirley X. Qian, MS; Jacqueline H. Boudreau, MPH; Donald R. Miller, ScD; Christopher G. Slatore, MD, MS; Renda Soylemez Wiener, MD, MPH
GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma
Authors: Mónica P de Andrés, Richard J Jackson, Irene Felipe, Sladjana Zagorac, Christian Pilarsky, Anna Melissa Schlitter, Jaime Martinez de Villareal, Gun Ho Jang, Eithne Costello, Steve Gallinger, Paula Ghaneh, William Greenhalf, Thomas Knösel, Daniel H Palmer, Petra Ruemmele, Wilko Weichert, Markus Buechler, Thilo Hackert, John P Neoptolemos, Faiyaz Notta, Núria Malats, Paola Martinelli, Francisco X Real
Journal: Gut (2022)

Objective GATA6 is a key regulator of the classical phenotype in pancreatic ductal adenocarcinoma (PDAC). Low GATA6 expression associates with poor patient outcome. GATA4 is the second most expressed GATA factor in the pancreas. We assessed whether, and how, GATA4 contributes to PDAC phenotype and analysed the association of expression with outcome and response to chemotherapy. Design We analysed PDAC transcriptomic data, stratifying cases according to GATA4 and GATA6 expression and identified differentially expressed genes and pathways. The genome-wide distribution of GATA4 was assessed, as well as the effects of GATA4 knockdown. A multicentre tissue microarray study to assess GATA4 and GATA6 expression in samples (n=745) from patients with resectable was performed. GATA4 and GATA6 levels were dichotomised into high/low categorical variables; association with outcome was assessed using univariable and multivariable Cox regression models. Results GATA4 messenger RNA is enriched in classical, compared with basal-like tumours. We classified samples in 4 groups as high/low for GATA4 and GATA6 . Reduced expression of GATA4 had a minor transcriptional impact but low expression of GATA4 enhanced the effects of GATA6 low expression. GATA4 and GATA6 display a partially overlapping genome-wide distribution, mainly at promoters. Reduced expression of both proteins in tumours was associated with the worst patient survival. GATA4 and GATA6 expression significantly decreased in metastases and negatively correlated with basal markers. Conclusions GATA4 and GATA6 cooperate to maintain the classical phenotype. Our findings provide compelling rationale to assess their expression as biomarkers of poor prognosis and therapeutic response.
Biopsy and blood-based molecular biomarker of inflammation in IBD
Authors: Carmen Argmann, Ruixue Hou, Ryan C Ungaro, Haritz Irizar, Zainab Al-Taie, Ruiqi Huang, Roman Kosoy, Swati Venkat, Won-Min Song, Antonio F Di'Narzo, Bojan Losic, Ke Hao, Lauren Peters, Phillip H Comella, Gabrielle Wei, Ashish Atreja, Milind Mahajan, Alina Iuga, Prerak T Desai, Patrick Branigan, Aleksandar Stojmirovic, Jacqueline Perrigoue, Carrie Brodmerkel, Mark Curran, Joshua R Friedman, Amy Hart, Esi Lamousé-Smith, Jan Wehkamp, Saurabh Mehandru, Eric E Schadt, Bruce E Sands, Marla C Dubinsky, Jean-Frederic Colombel, Andrew Kasarskis, Mayte Suárez-Fariñas
Journal: Gut (2022)

Objective IBD therapies and treatments are evolving to deeper levels of remission. Molecular measures of disease may augment current endpoints including the potential for less invasive assessments. Design Transcriptome analysis on 712 endoscopically defined inflamed (Inf) and 1778 non-inflamed (Non-Inf) intestinal biopsies (n=498 Crohn’s disease, n=421 UC and 243 controls) in the Mount Sinai Crohn’s and Colitis Registry were used to identify genes differentially expressed between Inf and Non-Inf biopsies and to generate a molecular inflammation score (bMIS) via gene set variance analysis. A circulating MIS (cirMIS) score, reflecting intestinal molecular inflammation, was generated using blood transcriptome data. bMIS/cirMIS was validated as indicators of intestinal inflammation in four independent IBD cohorts. Results bMIS/cirMIS was strongly associated with clinical, endoscopic and histological disease activity indices. Patients with the same histologic score of inflammation had variable bMIS scores, indicating that bMIS describes a deeper range of inflammation. In available clinical trial data sets, both scores were responsive to IBD treatment. Despite similar baseline endoscopic and histologic activity, UC patients with lower baseline bMIS levels were more likely treatment responders compared with those with higher levels. Finally, among patients with UC in endoscopic and histologic remission, those with lower bMIS levels were less likely to have a disease flare over time. Conclusion Transcriptionally based scores provide an alternative objective and deeper quantification of intestinal inflammation, which could augment current clinical assessments used for disease monitoring and have potential for predicting therapeutic response and patients at higher risk of disease flares.